Use of hydroxyeicosatetraenoic acid compounds to treat ophthalmic inflammatory disorders

ABSTRACT

The topical use of HETE compounds to treat ophthalmic inflammatory disorders involving cytokines is disclosed.

This application claims priority from U.S. Provisional Application, U.S.Ser. No. 60/389,115, filed Jun. 14, 2002.

The present invention is directed to the use of hydroxyeicosatetraenoicacid compounds to treat ophthalmic inflammation. In particular, theinvention relates to the use of such analogs in patients that are notsuffering from dry eye for the treatment and prevention of ophthalmicinflammatory disorders involving cytokine secretion.

BACKGROUND OF THE INVENTION

15-Hydroxyeicosatetraenoic acid (“15-HETE”) is known to have inhibitoryeffects on leukotriene B4 production or its activity. See, for example,Zhu, et al., Skin Pharmacology and Applied Skin Physiology, 13(5):235-45(September-October 2000); and Heitmann, et al., ExperimentalDermatology, 4(2):74-8 (April 1995). 15-HETE is also reported to haveminor anti-inflammatory properties in colitis. See Van Dijk, et al.,Agents and Actions, 38 Spec. No. C120-1 (1993).

U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containinghydroxyeicosatetraenoic acid (“HETE”) derivatives and methods of usingthem topically for treating dry eye. Yanni et al. discovered thatcompositions comprising HETE derivatives increase ocular mucin secretionand are thus useful in treating dry eye.

Other than the use of 15-HETE and certain analogs for treating dry eye,HETE compounds have not been reported to be useful in treatinginflammatory conditions of the eye, particularly in treating conditionsinvolving the production of pro-inflammatory cytokines. Reports of theeffects of 15-HETE and analogs of 15-HETE on cytokine inhibition inother tissues are varied. See, for example, Denizot, et al., Cytokine,11(8):606-10 (August 1999) (“ . . . 15-HETE (1 μM to 0.1 nM) [has] noeffect on the spontaneous and serum-induced production of IL-8 by humanbone marrow stromal cells”); Denizot, et al., Cytokine, 10(10):781-5(October 1998) (“ . . . 15-HETE . . . [has] no effect on thespontaneous, serum- and cytokine-induced IL-6 synthesis by bone marrowstromal cells; and WO 96/11908, which discloses that certain modifiedpolyunsaturated fatty acids have the ability to suppress cytokineproduction and cytokine action and are useful as anti-malarial,anti-infective or anti-inflammatory agents. WO 96/11908 does not mentionany ophthalmic inflammatory disorders.

SUMMARY OF THE INVENTION

The present invention is directed to methods of using HETE compounds totreat or prevent ophthalmic inflammatory conditions in patients that arenot suffering from dry eye. In particular, the present invention isdirected toward the topical ophthalmic use of HETE compounds to treat orprevent ophthalmic inflammatory conditions involving cytokines. Suchophthalmic inflammatory conditions include, but are not limited to,conjunctivitis; iritis; uveitis; episcleritis; scleritis; keratitis;endophthalmitis; and blepharitis.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “HETE compound” or “HETE compounds” means a compound offormulas I-XI.

I-III:

wherein:

X is O⁻M⁺, OR or NHR′;

M⁺ is Na⁺, K⁺, Li⁺, Cs⁺, and (A)₄N⁺; and A is independently H, alkyl,cycloalkyl, (cycloalkyl)alkyl, alkyl(cycloalkyl), aryl, arylalkyl,heteroaryl, or (A)₄N⁺ forms a heteroaryl, heterocycloalkenyl orheterocycloalkyl ring;

R is H, substituted or unsubstituted alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is madewith a moiety selected from the group consisting of: alkyl, halogen,hydroxy and functionally modified hydroxy;

R′ is H, substituted or unsubstituted alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitution is madewith a moiety selected from the group consisting of: alkyl, halogen,hydroxy and functionally modified hydroxy; and

Y is

wherein R″ is H or C(O)R;

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂—Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H, or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

K is C₂-C₈ alkyl, alkenyl, or alkynyl, or a C₃-C₈ allenyl group;

A and X are the same or different and are a direct bond, CH₂, NR⁷, O, orS, with the proviso that at least one of A and X is NR⁷, O, or S;

B is H, or BB together comprises a double bonded O, S, or NR⁸, with theproviso that BB comprises a double bonded O, S, or NR⁸ when A and X arethe same or different and are NR⁷, O, or S; wherein:

NR⁷ and NR⁸ are the same or different and comprise a functionallymodified amino group, e.g., R⁷ and R⁸ are the same or different and areH, alkyl, cycloalkyl, aryl, aralkyl, acyl, OH, or alkoxy;

p is 0 or 1;

D-E, G-H are the same or different and are CH₂CH₂, CH═CH, or C≡C; and

Y is C(O) (i.e. a carbonyl group) or Y is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹, or 2,3,4,5-tetrazol-1-yl, where:

R is H or a pharmaceutically acceptable cation, or CO₂R forms apharmaceutically acceptable ester moiety;

NR²R³, NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group;

OR⁴ comprises a free or functionally modified hydroxy group;

Hal is F, Cl, Br, or I;

R²⁰ is H, alkyl, acyl;

R²¹ is H or a pharmaceutically acceptable cation, or COSR²¹ forms apharmaceutically acceptable thioester moiety;

A is L₁-A₁-L₂, L₁-A₂-L₂, L₃-A₂-L₄, or L₅-A₂—L₃;

A₁ is CH₂CH₂;

A₂ is

L₁ is CH₂-B-D;

B and D are the same or different and are CH₂CH₂, CH═CH, or C≡C;

L₂ is CH₂-K-CH₂CH₂;

K is CH₂CH₂, CH═CH, or C≡C;

L₃ is CH₂CH₂CH₂, CH₂CH═CH, CH₂C≡C, CH═CHCH₂, C≡CCH₂, or CH═C═CH;

L₄ is X—CH₂CH₂;

X is CH₂CH₂CH═CH, CH₂CH₂C≡C, CH₂CH₂CH₂CH₂, CH₂CH═CHCH₂, CH₂C≡CCH₂,CH═CHCH₂CH₂, C≡CCH₂CH₂, CH₂CH═C═CH, or CH═C═CHCH₂;

L₅ is CH₂CH₂-B-D; and

Y is C(O) (i.e. a carbonyl group) or Y is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

X is C₂-C₅ alkyl, alkynyl, or alkenyl or a C₃-C₅ allenyl group;

Y is H, free or functionally modified hydroxy group, halo,trihalomethyl, free or functionally modified amino group, free orfunctionally modified thiol group, C(O)R⁷, or alkyl;

R⁷ is H, OH, alkyl, alkoxy, amino, alkylamino or alkoxyamino;

A is a direct bond or C₁₋₃ alkyl;

B is CH₂CH₂, cis- or trans-CH═CH, or C≡C; and

one of D and D¹ is H and the other is a free or functionally modified OHgroup, or DD¹ together comprises a double bonded oxygen;

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

E—D is CH₂CH₂CH₂ or cis-CH₂CH═CH; or E is trans-CH═CH and D is CH(OH) ineither configuration, wherein the OH is free or functionally modified;or E is CH₂CH₂ and D is a direct bond;

p is 1 or 3 when E-D is CH₂CH₂CH₂ or cis-CH₂CH═CH, or when E istrans-CH═CH and D is CH(OH) in either configuration, wherein the OH isfree or functionally modified; or p is 0 when E is CH₂CH₂ and D is adirect bond;

G-T is CH₂CH₂, CH(SR⁷)CH₂ or trans-CH═CH;

R⁷ is H, alkyl, aryl, aralkyl, cycloalkyl or acyl;

Y is CH(OH) in either configuration, in which the OH is free offunctionally modified, or C═O (i.e., a carbonyl group);

n is 0, 2 or 4; and

Z is CH₃, CO₂R, CONR²R³ or CH₂OR⁴;

wherein:

R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

n is 0 or 2;

X is O, S(O)_(p), NR⁷ or CH₂, with the proviso that X cannot be CH₂ whenn is 0;

p is 0, 1 or 2;

NR⁷ comprises a free or functionally modified amino group, e.g., R⁷ isH, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy,

A-B, D-E, G-T and J-K are the same or different and are CH₂CH₂, CH═CH orC≡C, with the proviso that at least one of A-B, D-E, G-T and J-K must beCH═CH or C≡C; and

Y is C(O) (i.e., a carbonyl), or Y is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

A, B, C and D are the same or different and are C₁-C₅ alkyl, alkenyl, oralkynyl or a C₃-C₅ allenyl group;

X is C(O) (i.e. a carbonyl group) or X is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein:

R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein:

R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester;

NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy;

OR⁴ comprises a free or functionally modified hydroxy group, e.g., R⁴ isH, acyl; alkyl, cycloalkyl, aralkyl, or aryl;

Hal is F, Cl, Br or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester;

n is 0 or 2;

A, B, C and D is C₁-C₅ alkyl, alkenyl, or alkynyl or a C₃-C₅ allenylgroup;

Y is

wherein R⁸ is H or CH₃, and

X is CH₂, CH(CH₃) or C(CH₃)₂; or

Y is CH₂, CH(CH₃) or C(CH₃)₂, and X is

wherein R⁸ is H or CH₃, with the proviso that Y cannot be CH₂ when X is

and

R⁷O comprises a free or functionally modified hydroxy group; and

wherein:

R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂, CH₂SR²⁰,COSR²¹, or 2,3,4,5-tetrazol-1-yl, where:

R is H or a pharmaceutically acceptable cation, or CO₂R forms apharmaceutically acceptable ester moiety;

NR²R³, NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group;

OR⁴ comprises a free or functionally modified hydroxy group;

Hal is F, Cl, Br, or I;

SR²⁰ comprises a free or functionally modified thiol group;

R²¹ is H or a pharmaceutically acceptable cation, or COSR²¹ forms apharmaceutically acceptable thioester moiety;

A, B, C, D are the same or different and are C₁-C₅ alkyl, C₂-C₅ alkenyl,C₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group;

E is

where OR⁷ comprises a free or functionally modified hydroxy group;

X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and

Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl,acyl, or

a free or functionally modified hydroxy, amino, or thiol group; or

X—Y=(CH₂)_(p)Y¹; where p=0-6; and

wherein:

W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q), CH═N, orCH₂NR⁸; where q=0-2, and R⁸=H, alkyl, or acyl;

Z=H, alkyl, acyl, halo, trihalomethyl, or a free or functionallymodified amino, thiol, or hydroxy group; and

————=single or double bond;

or X—Y=cyclohexyl.

Preferred HETE compounds include the compounds of formulas I-III whereinX is a pharmaceutically acceptable salt containing a cation selectedfrom the group consisting of: Na⁺; K⁺; Li⁺; Cs⁺; and (A)₄N⁺; and A isindependently H, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring.

Included within the scope of the present invention are the individualenantiomers of the HETE compounds, as well as their racemic andnon-racemic mixtures. The individual enantiomers can beenantioselectively synthesized from the appropriate enantiomericallypure or enriched starting material by means such as those describedbelow. Alternatively, they may be enantioselectively synthesized fromracemic/non-racemic or achiral starting materials. (AsymmetricSynthesis; J. D. Morrison and J. W. Scott, Eds.; Academic PressPublishers: New York, 1983-1985, volumes 1-5; Principles of AsymmetricSynthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers:Amsterdam, 1996). They may also be isolated from racemic and non-racemicmixtures by a number of known methods, e.g. by purification of a sampleby chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G.Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations byHPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or byenantioselective hydrolysis of a carboxylic acid ester sample by anenzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1(1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers substantially free of theirrespective enantiomers.

The term “free hydroxy group” means an OH. The term “functionallymodified hydroxy group” means an OH which has been functionalized toform: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl,alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl groupis substituted for the hydrogen; an ester, in which an acyl group issubstituted for the hydrogen; a carbamate, in which an aminocarbonylgroup is substituted for the hydrogen; or a carbonate, in which anaryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, oralkynyloxy-carbonyl group is substituted for the hydrogen. Preferredmoieties include OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,and OC(O)C₂H₅.

The term “free amino group” means an NH₂. The term “functionallymodified amino group” means an NH₂ which has been functionalized toform: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-,alkynyl-, or hydroxy-amino group, wherein the appropriate group issubstituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-,cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-,heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriategroup is substituted for one or both of the hydrogens; an amide, inwhich an acyl group is substituted for one of the hydrogens; acarbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-,heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, oralkynyl-carbonyl group is substituted for one of the hydrogens; or aurea, in which an aminocarbonyl group is substituted for one of thehydrogens. Combinations of these substitution patterns, for example anNH₂ in which one of the hydrogens is replaced by an alkyl group and theother hydrogen is replaced by an alkoxycarbonyl group, also fall underthe definition of a functionally modified amino group and are includedwithin the scope of the present invention. Preferred moieties includeNH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, and NH(OCH₃).

The term “free thiol group” means an SH. The term “functionally modifiedthiol group” means an SH which has been functionalized to form: athioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl,cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group issubstituted for the hydrogen; or a thioester, in which an acyl group issubstituted for the hydrogen. Preferred moieties include SH, SC(O)CH₃,SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃.

The term “acyl” represents a group that is linked by a carbon atom thathas a double bond to an oxygen atom and a single bond to another carbonatom.

The term “alkyl” includes straight or branched chain aliphatichydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Thealkyl groups may be interrupted by one or more heteroatoms, such asoxygen, nitrogen, or sulfur, and may be substituted with other groups,such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.Preferred straight or branched alkyl groups include methyl, ethyl,propyl, isopropyl, butyl and t-butyl.

The term “cycloalkyl” includes straight or branched chain, saturated orunsaturated aliphatic hydrocarbon groups which connect to form one ormore rings, which can be fused or isolated. The rings may be substitutedwith other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, orlower alkyl. Preferred cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “C₁-C₅ cyclopropyl” means an alkyl chain of 1 to 5 carbon atomscontaining a cyclopropyl group wherein the cyclopropyl group may start,be contained in or terminate the alkyl chain.

The term “heterocycloalkyl” refers to cycloalkyl rings that contain atleast one heteroatom such as O, S, or N in the ring, and can be fused orisolated. The rings may be substituted with other groups, such ashalogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferredheterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl,piperazinyl, and tetrahydropyranyl.

The term “alkenyl” includes straight or branched chain hydrocarbongroups having 1 to 15 carbon atoms with at least one carbon-carbondouble bond, the chain being optionally interrupted by one or moreheteroatoms. The chain hydrogens may be substituted with other groups,such as halogen. Preferred straight or branched alkenyl groups include,allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

The term “cycloalkenyl” includes straight or branched chain, saturatedor unsaturated aliphatic hydrocarbon groups which connect to form one ormore non-aromatic rings containing a carbon-carbon double bond, whichcan be fused or isolated. The rings may be substituted with othergroups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferredcycloalkenyl groups include cyclopentenyl and cyclohexenyl.

The term “heterocycloalkenyl” refers to cycloalkenyl rings which containone or more heteroatoms such as O, N, or S in the ring, and can be fusedor isolated. The rings may be substituted with other groups, such ashalogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferredheterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, anddihydrofuranyl.

The term “carbonyl group” represents a carbon atom double bonded to anoxygen atom, wherein the carbon atom has two free valencies.

The term “aminocarbonyl” represents a free or functionally modifiedamino group bonded from its nitrogen atom to the carbon atom of acarbonyl group, the carbonyl group itself being bonded to another atomthrough its carbon atom.

The term “lower alkyl” represents alkyl groups containing one to sixcarbons (C₁-C₆).

The term “halogen” represents fluoro, chloro, bromo, or iodo.

The term “aryl” refers to carbon-based rings which are aromatic. Therings may be isolated, such as phenyl, or fused, such as naphthyl. Thering hydrogens may be substituted with other groups, such as loweralkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl,3-chlorophenyl, and 4-fluorophenyl.

The term “heteroaryl” refers to aromatic hydrocarbon rings which containat least one heteroatom such as O, S, or N in the ring. Heteroaryl ringsmay be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.The heteroaryl ring(s) hydrogens or heteroatoms with open valency may besubstituted with other groups, such as lower alkyl or halogen. Examplesof heteroaryl groups include imidazole, pyridine, indole, quinoline,furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, anddihydrobenzindole.

The terms “aryloxy”, “heteroaryloxy”, “alkoxy”, “cycloalkoxy”,“heterocycloalkoxy”, “alkenyloxy”, “cycloalkenyloxy”,“heterocycloalkenyloxy”, and “alkynyloxy” represent an aryl, heteroaryl,alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,heterocycloalkenyl, or alkynyl group, respectively, attached through anoxygen linkage.

The terms “alkoxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl”,“cycloalkoxycarbonyl”, “heterocycloalkoxycarbonyl”,“alkenyloxycarbonyl”, “cycloalkenyloxycarbonyl”,“heterocycloalkenyloxycarbonyl”, and “alkynyloxycarbonyl” represent analkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy,alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group,respectively, bonded from its oxygen atom to the carbon of a carbonylgroup, the carbonyl group itself being bonded to another atom throughits carbon atom.

According to the methods of the present invention a HETE compound offormulas I-XI is applied topically to the eye. The compositions used inthe methods of the present invention comprise a pharmaceuticallyeffective amount of one or more HETE compounds of formulas I-XI and apharmaceutically acceptable carrier. Suitable pharmaceutical carriersare known in the art and include, but are not limited to, ophthalmicallyacceptable solutions, suspensions and other dosage forms for topicaladministration. Aqueous solutions are generally preferred, based on easeof formulation, biological compatibility, as well as a patient's abilityto easily administer such compositions by means of instilling one to twodrops of the solutions in the affected eyes. However, the compositionsmay also be suspensions, viscous or semi-viscous gels, or other types ofsolid or semi-solid compositions. Suspensions may be preferred forcompounds of formulas I-XI which are less soluble in water.

As used herein, the term “pharmaceutically effective amount” refers toan amount of one or more compounds of formulas I-XI that, whenadministered to a patient, reduces, eliminates or prevents ophthalmicinflammation. Generally, the compounds of formulas I-XI will becontained in a composition of the present invention in a concentrationrange of about 0.000001 to 10 percent weight/volume (“% w/v”).Preferably, the compositions will contain one or more compounds offormulas I-XI in a concentration of from about 0.00001-0.01% w/v.

Various tonicity agents may be included in the compositions of thepresent invention to adjust tonicity, preferably to that of naturaltears for ophthalmic compositions. For example, sodium chloride,potassium chloride, magnesium chloride, calcium chloride, dextroseand/or mannitol may be added to the composition to approximatephysiological tonicity. Such an amount of tonicity agent will vary,depending on the particular agent to be added. In general, however, thecompositions will have one or more tonicity agents in a totalconcentration sufficient to cause the composition to have an osmolalityof about 200-400 mOsm.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate,sodium citrate, sodium borate or boric acid) may be added to thecompositions to prevent pH drift under storage conditions. Theparticular concentration will vary, depending on the agent employed. Ingeneral, however, the buffering agent will be present in an amountsufficient to hold the pH within the range 6.5-8.0, preferably 6.8-7.6.

Antioxidants may be added to compositions of the present invention toprotect the compounds of formulas I-XI from oxidation during storageand/or or to provide antioxidant effects in the eye. Examples of suchantioxidants include, but are not limited to, vitamin E and analogsthereof, ascorbic acid and derivatives, and butylated hydroxyanisole(BHA).

The compositions of the present invention may be used to treat orprevent ophthalmic inflammatory conditions involving cytokine secretion.Such conditions include, but are not limited to, non-infectiouskeratoconjunctivitis (including, but not limited to, seasonal allergicconjunctivitis, atopic keratoconjunctivitis, vernalkeratoconjunctivitis, contact dermatoconjunctivitis, giant papillaryconjunctivitis, contact lens-induced keratoconjunctivitis, superiorlimbic keratoconjunctivitis, toxic conjunctivitis, ocular cicatricialpemphigoid, and Thygeson's superficial punctate keratopathy), uveitis,episcleritis, scleritis, iritis, blepharitis, keratitis,endophthalmitis, canaliculitis, dacryocystitis, preseptal cellulitis,orbital cellulitis. seborrheic blepharitis, meibomian gland dysfunction,acne rosacea, filamentary keratopathy, neurotrophic keratopathy, cornealerosions, corneal dystrophies, iridocorneal endothelial syndrome,noninfectious ulcerative keratitis. Such inflammatory conditionsinvolving cytokine secretion also include inflammation due to oculartrauma, including, but not limited to inflammation due to cornealabrasions, corneal foreign body, corneal laceration and chemical burn,and iatrogenic inflammatory conditions related to post-LASIK,post-LASEK, post-PRK, post-cataract surgery, post-glaucoma filtrationsurgery. Such inflammatory conditions involving cytokine secretion alsoinclude inflammation due to degeneration and corneal ectactic disorders,including, but not limited to, ptyrygium, pinguecula, band-shapedkeratopathy, Salzmann's nodular degeneration, keratoconus, and Terrien'smarginal degeneration. Such inflammatory conditions involving cytokinesecretion also include, but are not limited to, entropion, ectropion,trichiasis, lagophthalmos and floppy eyelid syndrome.

The compositions of the present invention also may be used alone or incombination with antimicrobial or antiviral agents in diseases primarilyinfectious in nature but involving an inflammatory component, including,but not limited to infectious conjunctivitis and infectious keratitisconditions, such as bacterial conjunctivitis, viral conjunctivitis,chlamydial conjunctivitis, fungal conjunctivitis, bacterial keratitis,fungal keratitis and acanthamoeba keratitis, herpetic diseases of theeye, infectious endophthalmitis, and staphyloccocal blepharitis.

Preferably, the compositions of the present invention are used to treatophthalmic inflammatory conditions selected from the group consisting ofconjunctivitis (non-infectious keratoconjunctivitis and infectiousconjunctivitis); iritis; uveitis; episcleritis; scleritis; keratitis;endophthalmitis; blepharitis; and iatrogenic inflammatory conditions.

The following examples are presented to illustrate various aspects ofthe present invention, but are not intended to limit the scope of theinvention in any respect.

EXAMPLE 1

Ingredient Amount (% w/v) Compound of formulas I-XI 0.00001-0.01 Ethanol0.0505 Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH = 7.5Purified Water q.s. 100%

The above composition is prepared by the following method. The batchquantities of polyoxyl 40 stearate, boric acid, sodium chloride,disodium edetate, and polyquaternium-1 are weighed and dissolved bystirring in 90% of the batch quantity of purified water. The pH isadjusted to 7.5±0.1 with NaOH and/or HCl. Under yellow light or reducedlighting, the batch quantity of the compound of formulas I-XI as a stocksolution in ethanol and the additional quantity of ethanol necessary forthe batch are measured and added. Purified water is added to q.s. to100%. The mixture is stirred for five minutes to homogenize and thenfiltered through a sterilizing filter membrane into a sterile recipient.Preferably, the above process is performed using glass, plastic or othernon-metallic containers or containers lined with such materials.

EXAMPLE 2

Ingredient Amount (% w/v) Compound of formulas I-XI 0.00001-0.01Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75 DisodiumEdetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH = 6.5-8 PurifiedWater q.s. 100%

The above formulation may be made by a method similar to the methoddescribed in Example 1.

EXAMPLE 3

Ingredient Amount (% w/v) Compound of formulas I-XI 0.00001-0.01Polyoxyl 40 Stearate 0.1 Ethanol  0.005-0.2 Boric Acid 0.25 SodiumChloride 0.75 NaOH/HCl q.s., pH = 6.5-8 Purified Water q.s. 100%

The above formulation may be made by a method similar to the methoddescribed in Example 1.

EXAMPLE 4

The following is an example of a composition of the present inventionusing an artificial tears carrier:

Ingredient Amount (% w/v) Compound of formulas I-XI 0.00001-0.01 HPMC0.3 Dextran 70 0.1 Sodium Chloride 0.8 Potassium Chloride 0.12 DibasicSodium Phosphate 0.025 Disodium EDTA 0.01 Polyquaternium-1 0.001 + 10%excess Purified Water Qs NaOH/HCl qs to pH 6-8

The above formulation may be made by a method similar to the methoddescribed in Example 1.

EXAMPLE 5

Primary human corneal fibroblast cells were obtained from one donor andgrown to confluence in Ham's F-10 medium. Fibroblasts were transferredto serum-free media and were pretreated for 30 minutes with variousconcentrations of 15(S)-HETE. The cells were then stimulated with 10ng/ml IL-1β for 3 hours and aliquots of the supernatants were assayedfor IL-6 by ELISA. Data were normalized by the amount of double strandedDNA (dsDNA) extracted from the cells. The results are shown below inTable 1.

TABLE 1 Concentration of % Inhibition of IL-6 15(S)-HETE (μg) (pg/μgdsDNA) 0.5 53.1 1 67.9* 2 88.6** 3 90.4** *p < 0.05, **p < 0.01 Two-tailDunnett's t-test compared to IL-1β stimulated cells

The results shown in Table 1 demonstrate that 15-HETE dose-dependentlyinhibited IL-6 release from primary human corneal fibroblast cells. TheIC₅₀ for IL-6 inhibition was less than 0.5 μM.

The invention in its broader aspects is not limited to the specificdetails shown and described above. Departures may be made from suchdetails within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing itsadvantages.

What is claimed is:
 1. A method of treating ophthalmic inflammatorydisorders in a patient that is not suffering from dry eye, wherein theophthalmic inflammatory disorder is selected from the group consistingof conjunctivitis; iritis; uveitis; episcleritis; scleritis; keratitis;endophthalmitis; blepharitis; and iatrogenic inflammatory conditions,and wherein the method comprises topically administering to the patienta composition comprising a HETE compound of formulas I-XI: I-III:

wherein: X is O⁻M⁺, OR or NHR′; M⁺ is Na⁺, K⁺, Li⁺, Cs⁺, and (A)₄N⁺; andA is independently H, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R is H,substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,arylalkyl, wherein the substitution is made with a moiety selected fromthe group consisting of: alkyl, halogen, hydroxy and functionallymodified hydroxy; R′ is H, substituted or unsubstituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl, wherein the substitutionis made with a moiety selected from the group consisting of: alkyl,halogen, hydroxy and functionally modified hydroxy; and Y is

wherein R″ is H or C(O)R;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂—Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprises a free orfunctionally modified hydroxy group, e.g., R⁴ is H, acyl; alkyl,cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br or I; SR²⁰ comprises afree or functionally modified thiol group; R²¹ is H, or COSR²¹ forms apharmaceutically acceptable salt or a pharmaceutically acceptablethioester; K is C₂-C₈ alkyl, alkenyl, or alkynyl, or a C₃-C₈ allenylgroup; A and X are the same or different and are a direct bond, CH₂,NR⁷, O, or S, with the proviso that at least one of A and X is NR⁷, O,or S; B is H, or BB together comprises a double bonded O, S, or NR⁸,with the proviso that BB comprises a double bonded O, S, or NR⁸ when Aand X are the same or different and are NR⁷, O, or S; wherein: NR⁷ andNR⁸ are the same or different and comprise a functionally modified aminogroup, e.g., R⁷ and R⁸ are the same or different and are H, alkyl,cycloalkyl, aryl, aralkyl, acyl, OH, or alkoxy; p is 0 or 1; D-E, G-Hare the same or different and are CH₂CH₂, CH═CH, or C≡C; and Y is C(O)(i.e. a carbonyl group) or Y is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H or apharmaceutically acceptable cation, or CO₂R forms a pharmaceuticallyacceptable ester moiety; NR²R³, NR⁵R⁶ are the same or different andcomprise a free or functionally modified amino group; OR⁴ comprises afree or functionally modified hydroxy group; Hal is F, Cl, Br, or I; R²⁰is H, alkyl, acyl; R²¹ is H or a pharmaceutically acceptable cation, orCOSR²¹ forms a pharmaceutically acceptable thioester moiety; A isL₁-A₁-L₂, L₁-A₂-L₂, L₃-A₂-L₄, or L₅-A₂—L₃; A₁ is CH₂CH₂; A₂ is

L₁ is CH₂-B-D; B and D are the same or different and are CH₂CH₂, CH═CH,or C≡C; L₂ is CH₂-K-CH₂CH₂; K is CH₂CH₂, CH═CH, or C≡C; L₃ is CH₂CH₂CH₂,CH₂CH═CH, CH₂C≡C, CH═CHCH₂, C≡CCH₂, or CH═C═CH; L₄ is X—CH₂CH₂; X isCH₂CH₂CH═CH, CH₂CH₂C≡C, CH₂CH₂CH₂CH₂, CH₂CH═CHCH₂, CH₂C≡CCH₂,CH═CHCH₂CH₂, C≡CCH₂CH₂, CH₂CH═C═CH, or CH═C═CHCH₂; L₅ is CH₂CH₂-B-D; andY is C(O) (i.e. a carbonyl group) or Y is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprises a free orfunctionally modified hydroxy group, e.g., R⁴ is H, acyl; alkyl,cycloalkyl, aralkyl or aryl; Hal is F, Cl, Br or I; SR²⁰ comprises afree or functionally modified thiol group; R²¹ is H or COSR²¹ forms apharmaceutically acceptable salt or a pharmaceutically acceptablethioester; X is C₂-C₅ alkyl, alkynyl, or alkenyl or a C₃-C₅ allenylgroup; Y is H, free or functionally modified hydroxy group, halo,trihalomethyl, free or functionally modified amino group, free orfunctionally modified thiol group, C(O)R⁷, or alkyl; R⁷ is H, OH, alkyl,alkoxy, amino, alkylamino or alkoxyamino; A is a direct bond or C₁₋₃alkyl; B is CH₂CH₂, cis- or trans-CH═CH, or C≡C; and one of D and D¹ isH and the other is a free or functionally modified OH group, or DD¹together comprises a double bonded oxygen;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprises a free orfunctionally modified hydroxy group, e.g., R⁴ is H, acyl; alkyl,cycloalkyl, aralkyl or aryl; Hal is F, Cl, Br or I; SR²⁰ comprises afree or functionally modified thiol group; R²¹ is H or COSR²¹ forms apharmaceutically acceptable salt or a pharmaceutically acceptablethioester; E-D is CH₂CH₂CH₂ or cis-CH₂CH═CH; or E is trans-CH═CH and Dis CH(OH) in either configuration, wherein the OH is free orfunctionally modified; or E is CH₂CH₂ and D is a direct bond; p is 1 or3 when E-D is CH₂CH₂CH₂ or cis-CH₂CH═CH, or when E is trans-CH═CH and Dis CH(OH) in either configuration, wherein the OH is free orfunctionally modified; or p is 0 when E is CH₂CH₂ and D is a directbond; G-T is CH₂CH₂, CH(SR⁷)CH₂ or trans-CH═CH; R⁷ is H, alkyl, aryl,aralkyl, cycloalkyl or acyl; Y is CH(OH) in either configuration, inwhich the OH is free of functionally modified, or C═O (i.e., a carbonylgroup); n is 0, 2 or 4; and Z is CH₃, CO₂R, CONR²R³ or CH₂OR⁴;

wherein: R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein: R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester; NR²R³ and NR⁵R⁶ are the same ordifferent and comprise a free or functionally modified amino group,e.g., R², R³, R⁵ and R⁶ are the same or different and are H, alkyl,cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at mostonly one of R² and R³ are OH or alkoxy and at most only one of R⁵ and R⁶are OH or alkoxy; OR⁴ comprises a free or functionally modified hydroxygroup, e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl; Hal isF, Cl, Br or I; SR²⁰ comprises a free or functionally modified thiolgroup; R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester; n is 0 or 2; X is O, S(O)_(p),NR⁷ or CH₂, with the proviso that X cannot be CH₂ when n is 0; p is 0, 1or 2; NR⁷ comprises a free or functionally modified amino group, e.g.,R⁷ is H, alkyl, cycloalkyl, aralkyl, aryl, OH or alkoxy, A-B, D-E, G-Tand J-K are the same or different and are CH₂CH₂, CH═CH or C≡C, with theproviso that at least one of A-B, D-E, G-T and J-K must be CH═CH or C≡C;and Y is C(O) (i.e., a carbonyl), or Y is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H or CO₂R formsa pharmaceutically acceptable salt or a pharmaceutically acceptableester; NR²R³ and NR⁵R⁶ are the same or different and comprise a free orfunctionally modified amino group, e.g., R², R³, R⁵ and R⁶ are the sameor different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy,with the proviso that at most only one of R² and R³ are OH or alkoxy andat most only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ comprises a free orfunctionally modified hydroxy group, e.g., R⁴ is H, acyl; alkyl,cycloalkyl, aralkyl, or aryl; Hal is F, Cl, Br or I; SR²⁰ comprises afree or functionally modified thiol group; R²¹ is H or COSR²¹ forms apharmaceutically acceptable salt or a pharmaceutically acceptablethioester; A, B, C and D are the same or different and are C₁-C₅ alkyl,alkenyl, or alkynyl or a C₃-C₅ allenyl group; X is C(O) (i.e. a carbonylgroup) or X is

wherein R⁹O constitutes a free or functionally modified hydroxy group;

wherein: R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein: R is H or CO₂R forms a pharmaceutically acceptable salt or apharmaceutically acceptable ester; NR²R³ and NR⁵R⁶ are the same ordifferent and comprise a free or functionally modified amino group,e.g., R², R³, R⁵ and R⁶ are the same or different and are H, alkyl,cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at mostonly one of R² and R³ are OH or alkoxy and at most only one of R⁵ and R⁶are OH or alkoxy; OR⁴ comprises a free or functionally modified hydroxygroup, e.g., R⁴ is H, acyl; alkyl, cycloalkyl, aralkyl, or aryl; Hal isF, Cl, Br or I; SR²⁰ comprises a free or functionally modified thiolgroup; R²¹ is H or COSR²¹ forms a pharmaceutically acceptable salt or apharmaceutically acceptable thioester; n is 0 or 2; A, B, C and D isC₁-C₅ alkyl, alkenyl, or alkynyl or a C₃-C₅ allenyl group; Y is

wherein R⁸ is H or CH₃, and X is CH₂, CH(CH₃) or C(CH₃)₂; or Y is CH₂,CH(CH₃) or C(CH₃)₂, and X is

wherein R⁸ is H or CH₃, with the proviso that Y cannot be CH₂ when X is

and R⁷O comprises a free or functionally modified hydroxy group; and

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H or apharmaceutically acceptable cation, or CO₂R forms a pharmaceuticallyacceptable ester moiety; NR²R³, NR⁵R⁶ are the same or different andcomprise a free or functionally modified amino group; OR⁴ comprises afree or functionally modified hydroxy group; Hal is F, Cl, Br, or I;SR²⁰ comprises a free or functionally modified thiol group; R²¹ is H ora pharmaceutically acceptable cation, or COSR²¹ forms a pharmaceuticallyacceptable thioester moiety; A, B, C, D are the same or different andare C₁-C₅ alkyl, C₂-C₅ alkenyl, C₁₋₅ cyclopropyl, C₂-C₅ alkynyl, or aC₃-C₅ allenyl group; E is

where OR⁷ comprises a free or functionally modified hydroxy group;X═(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and Y=a phenyl ring optionallysubstituted with alkyl, halo, trihalomethyl, acyl, or a free orfunctionally modified hydroxy, amino, or thiol group; orX—Y═(CH₂)_(p)Y¹; where p=0-6; and

wherein: W═CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; where q=0-2, and R⁸═H, alkyl, or acyl; Z═H, alkyl,acyl, halo, trihalomethyl, or a free or functionally modified amino,thiol, or hydroxy group; and — ═ single or double bond; orX—Y=cyclohexyl.
 2. The method of claim 1 wherein the HETE compound is acompound of formulas I-III.
 3. The method of claim 1 wherein the HETEcompound is a compound of formulas I-XI: I-III:

wherein: X is O⁻M⁺, OR or NHR′; M⁺ is Na⁺, K⁺, Li⁺, or Cs⁺; R is H, orsubstituted or unsubstituted C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,aryl, or arylalkyl, wherein the substitution is made with a moietyselected from the group consisting of: C₁₋₆ alkyl, fluoro, chloro,bromo, iodo, OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, andOC(O)C₂H₅; R′ is H, or substituted or unsubstituted C₁₋₁₅ alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, or arylalkyl, wherein thesubstitution is made with a moiety selected from the group consistingof: C₁₋₆ alkyl, fluoro, chloro, bromo, iodo, OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, and OC(O)C₂H₅; and Y is

wherein R″ is H or C(O)R;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂-Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, wherein: R is H, Na⁺, K⁺,Li⁺, Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl or alkoxy;A is independently H or C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R², R³, R⁵ andR⁶ are the same or different and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl, or alkoxy, with the proviso that at most only one of R²and R³ are OH or alkoxy and at most only one of R⁵ and R⁶ are OH oralkoxy; OR⁴ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅; Hal is F, Cl, Br or I; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅,SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹ is H or C₁₋₁₅ alkyl or aryl; K isC₂-C₈ alkyl, alkenyl, or alkynyl, or a C₃-C₈ allenyl group; A and X arethe same or different and are a direct bond, CH₂, NR⁷, O, or S, with theproviso that at least one of A and X is NR⁷, O, or S; B is H, or BBtogether comprises a double bonded O, S, or NR⁸, with the proviso thatBB comprises a double bonded O, S, or NR⁸ when A and X are the same ordifferent and are NR⁷, O, or S; wherein: R⁷ and R⁸ are the same ordifferent and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl, aryl, aralkyl,acyl, or alkoxy; p is 0 or 1; D-E, G-H are the same or different and areCH₂CH₂, CH═CH, or C≡C; and Y is C(O) or

wherein OR⁹ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H, Na⁺, K⁺, Li⁺,Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl or alkoxy; A isindependently H or C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R², R³, R⁵ andR⁶ are the same or different and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl, or alkoxy, with the proviso that at most only one of R²and R³ are OH or alkoxy and at most only one of R⁵ and R⁶ are OH oralkoxy; OR⁴ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅; Hal is F, Cl, Br, or I; R²⁰ is H or C₁₋₁₅ alkyl or acyl;R²¹ is H or C₁₋₁₅ alkyl or aryl; A is L₁-A₁-L₂, L₁-A₂-L₂, L₃-A₂-L₄, orL₅-A₂—L₃; A₁ is CH₂CH₂; A₂ is

L₁ is CH₂-B-D; B and D are the same or different and are CH₂CH₂, CH═CH,or C≡C; L₂ is CH₂-K-CH₂CH₂; K is CH₂CH₂, CH═CH, or C≡C; L₃ is CH₂CH₂CH₂,CH₂CH═CH, CH₂C≡C, CH═CHCH₂, C≡CCH₂, or CH═C═CH; L₄ is X—CH₂CH₂; X isCH₂CH₂CH═CH, CH₂CH₂C≡C, CH₂CH₂CH₂CH₂, CH₂CH═CHCH₂, CH₂C≡CCH₂,CH═CHCH₂CH₂, C≡CCH₂CH₂, CH₂CH═C═CH, or CH═C═CHCH₂; L₅ is CH₂CH₂-B-D; andY is C(O) or

wherein OR⁹ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H, Na⁺, K⁺, Li⁺,Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl or alkoxy; A isindependently H or C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R², R³, R⁵ andR⁶ are the same or different and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl, or alkoxy, with the proviso that at most only one of R²and R³ are OH or alkoxy and at most only one of R⁵ and R⁶ are OH oralkoxy; OR⁴ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅; Hal is F, Cl, Br or I; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅,SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹ is H or C₁₋₁₅ alkyl or aryl; X isC₂-C₅ alkyl, alkynyl, or alkenyl or a C₃-C₅ allenyl group; Y is H,OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, or OC(O)C₂H₅, Hal,C(Hal)₃, NH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, NH(OCH₃), SH,SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, SCH₂C(O)CH₃, C(O)R⁷, or C₁₋₅ alkyl;R⁷ is H, OH, or C₁₋₁₅ alkyl, alkoxy, amino, alkylamino or alkoxyamino; Ais a direct bond or C₁₋₃ alkyl; B is CH₂CH₂, cis- or trans-CH═CH, orC≡C; and one of D and D¹ is H and the other is OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, or OC(O)C₂H₅, or DD¹ togethercomprises a double bonded oxygen;

wherein: R¹ is CO₂R, CONR²R³ , CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H, Na⁺, K⁺, Li⁺,Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl or alkoxy; A isindependently H or C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R², R³, R⁵ andR⁶ are the same or different and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl, or alkoxy, with the proviso that at most only one of R²and R³ are OH or alkoxy and at most only one of R⁵ and R⁶ are OH oralkoxy; OR⁴ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅; Hal is F, Cl, Br or I; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅,SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹ is H or C₁₋₁₅ alkyl or aryl; E-D isCH₂CH₂CH₂ or cis-CH₂CH═CH; or E is trans-CH═CH and D is CH(X) in eitherconfiguration, wherein X is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃,OCH₂CH₃, OC(O)CH₃, or OC(O)C₂H₅; or E is CH₂CH₂ and D is a direct bond;p is 1 or 3 when E-D is CH₂CH₂CH₂ or cis-CH₂CH═CH, or when E istrans-CH═CH and D is CH(X) in either configuration; or p is 0 when E isCH₂CH₂ and D is a direct bond; G-T is CH₂CH₂, CH(SR⁷)CH₂ or trans-CH═CH;R⁷ is H, or C₁₋₁₅ alkyl, aryl, aralkyl, cycloalkyl or acyl; Y is CH(X)in either configuration, or C(O); n is 0, 2 or 4; and Z is CH₃, CO₂R,CONR²R³ or CH₂OR⁴;

wherein: R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein: R is H, Na⁺, K⁺, Li⁺, Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl or alkoxy; A is independently H or C₁₋₁₅ alkyl,cycloalkyl, (cycloalkyl)alkyl, alkyl(cycloalkyl), aryl, arylalkyl,heteroaryl, or (A)₄N⁺ forms a heteroaryl, heterocycloalkenyl orheterocycloalkyl ring; R², R³, R⁵ and R⁶ are the same or different andare H, OH, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl, or alkoxy, withthe proviso that at most only one of R² and R³ are OH or alkoxy and atmost only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ is OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, or OC(O)C₂H₅; Hal is F, Cl, Br orI; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹is H or C₁₋₁₅ alkyl or aryl; n is 0 or 2; X is O, S(O)_(p), NR⁷ or CH₂,with the proviso that X cannot be CH₂ when n is 0; p is 0, 1 or 2; R⁷ isH, OH or C₁₋₁₅ alkyl, cycloalkyl, aralkyl, aryl, or alkoxy, A-B, D-E,G-T and J-K are the same or different and are CH₂CH₂, CH═CH or C≡C, withthe proviso that at least one of A-B, D-E, G-T and J-K must be CH═CH orC≡C; and Y is C(O), or

wherein OR⁹ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅;

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹ or 2,3,4,5-tetrazol-1-yl, wherein: R is H, Na⁺, K⁺, Li⁺,Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl or alkoxy; A isindependently H or C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R², R³, R⁵ andR⁶ are the same or different and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl, or alkoxy, with the proviso that at most only one of R²and R³ are OH or alkoxy and at most only one of R⁵ and R⁶ are OH oralkoxy; OR⁴ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅; Hal is F, Cl, Br or I; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅,SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹ is H or C₁₋₁₅ alkyl or aryl; A, B, Cand D are the same or different and are C₁-C₅ alkyl, alkenyl, or alkynylor a C₃-C₅ allenyl group; X is C(O) or

wherein OR⁹ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅;

wherein: R¹ is (CH₂)_(n)CO₂R, (CH₂)_(n)CONR²R³, (CH₂)_(n)CH₂OR⁴,(CH₂)_(n)CH₂NR⁵R⁶, (CH₂)_(n)CH₂N₃, (CH₂)_(n)CH₂Hal, (CH₂)_(n)CH₂NO₂,(CH₂)_(n)CH₂SR²⁰, (CH₂)_(n)(COSR²¹ or (CH₂)_(n)-2,3,4,5-tetrazol-1-yl,wherein: R is H, Na⁺, K⁺, Li⁺, Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl or alkoxy; A is independently H or C₁₋₁₅ alkyl,cycloalkyl, (cycloalkyl)alkyl, alkyl(cycloalkyl), aryl, arylalkyl,heteroaryl, or (A)₄N⁺ forms a heteroaryl, heterocycloalkenyl orheterocycloalkyl ring; R², R³, R⁵ and R⁶ are the same or different andare H, OH, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl, or alkoxy, withthe proviso that at most only one of R² and R³ are OH or alkoxy and atmost only one of R⁵ and R⁶ are OH or alkoxy; OR⁴ is OH, OCH₂C(O)CH₃,OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, or OC(O)C₂H₅; Hal is F, Cl, Br orI; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹is H or C₁₋₁₅ alkyl or aryl; n is 0 or 2; A, B, C and D is C₁-C₅ alkyl,alkenyl, or alkynyl or a C₃-C₅ allenyl group; Y is

wherein R⁸ is H or CH₃, and X is CH₂, CH(CH₃) or C(CH₃)₂; or Y is CH₂,CH(CH₃) or C(CH₃)₂, and X is

wherein R⁸ is H or CH₃, with the proviso that Y cannot be CH₂ when X is

and R⁷O is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, orOC(O)C₂H₅; and

wherein: R¹ is CO₂R, CONR²R³, CH₂OR⁴, CH₂NR⁵R⁶, CH₂N₃, CH₂Hal, CH₂NO₂,CH₂SR²⁰, COSR²¹, or 2,3,4,5-tetrazol-1-yl, where: R is H, Na⁺, K⁺, Li⁺,Cs⁺, (A)₄N⁺, or C₁₋₁₅ alkyl, cycloalkyl, arylalkyl, aryl or alkoxy; A isindependently H or C₁₋₁₅ alkyl, cycloalkyl, (cycloalkyl)alkyl,alkyl(cycloalkyl), aryl, arylalkyl, heteroaryl, or (A)₄N⁺ forms aheteroaryl, heterocycloalkenyl or heterocycloalkyl ring; R², R³, R⁵ andR⁶ are the same or different and are H, OH, or C₁₋₁₅ alkyl, cycloalkyl,arylalkyl, aryl, or alkoxy, with the proviso that at most only one of R²and R³ are OH or alkoxy and at most only one of R⁵ and R⁶ are OH oralkoxy; OR⁴ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃,or OC(O)C₂H₅; Hal is F, Cl, Br or I; SR²⁰ is SH, SC(O)CH₃, SCH₃, SC₂H₅,SCH₂C(O)C₂H₅, and SCH₂C(O)CH₃; R²¹ is H or C-₁₋₁₅ alkyl or aryl; A, B,C, D are the same or different and are C₁-C₅ alkyl, C₂-C₅ alkenyl, C₁₋₅cyclopropyl, C₂-C₅ alkynyl, or a C₃-C₅ allenyl group; E is

where OR⁷ is OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, orOC(O)C₂H₅; X=(CH₂)_(m) or (CH₂)_(m)O, where m=1-6; and Y=a phenyl ringoptionally substituted with C₁₋₆ alkyl or acyl, Hal, C(Hal)₃, OH,OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃, OCH₂CH₃, OC(O)CH₃, OC(O)C₂H₅, NH₂,NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃, NHOH, NH(OCH₃), SH, SC(O)CH₃, SCH₃,SC₂H₅, SCH₂C(O)C₂H₅, or SCH₂C(O)CH₃; and X—Y=(CH₂)_(p)Y¹; where p=0-6;and

wherein: W=CH₂, O, S(O)_(q), NR⁸, CH₂CH₂, CH═CH, CH₂O, CH₂S(O)_(q),CH═N, or CH₂NR⁸; where q=0-2, and R⁸=H, or C₁₋₁₅ alkyl or acyl; Z=H,C₁₋₁₅ alkyl or acyl, Hal, C(Hal)₃, OH, OCH₂C(O)CH₃, OCH₂C(O)C₂H₅, OCH₃,OCH₂CH₃, OC(O)CH₃, OC(O)C₂H₅, NH₂, NHCH₃, NHC₂H₅, N(CH₃)₂, NHC(O)CH₃,NHOH, NH(OCH₃), SH, SC(O)CH₃, SCH₃, SC₂H₅, SCH₂C(O)C₂H₅, or SCH₂C(O)CH₃;and ————=single or double bond; or X—Y=cyclohexyl.
 4. The method ofclaim 1 wherein the HETE compound is present in the composition in aconcentration range of about 0.000001 to 10% w/v.
 5. The method of claim4 wherein the HETE compound is present in the composition in aconcentration range of about 0.00001-0.01% w/v.